Improvements in both the delivery of immunogens and the form of immunogens are needed to enhance the possibility of efficacy for potential HIV-1 vaccines. We are using the VEE vaccine vector system to target high-level expression of the immunogens to lymph nodes. In Project 2 we will explore ways of improving the form of the immunogen, especially the viral glycoprotein, to enhance the neutralizing antibody response. Much of the proposed work will be done using simian immunodeficiency virus (SIVsmH4) as a model primate 1entivirus. We will explore a number of issues dealing with strategies for enhancing the quality of the immune response to the viral Env protein. These will include: i) exploring ways to increase the level of expression; ii) altering the protein structure to expose important neutralizing sites; iii) manipulating carbohydrate addition sites to enhance a neutralizing response; iv) using HIV-I Env proteins that may naturally elicit a broad neutralizing response, and v) using multiple distinct HIV-l Env proteins to broaden the neutralizing response. Other studies will examine the quality of the response to proteins that remain cell-associated versus those that are secreted in a particulate form as virus-like particles. Finally, in anticipation of human trials, we will carry out a survey of extant viral sequences in recent seroconverters and in people who are likely unaware they are infected. These studies will provide important information about the design of an effect primate lentivirus vaccine and about the nature of the HIV- l target sequences against which protection must be elicited.